iwCAR-T 2025 | T-cell engagers and CARs in myeloid malignancies

David Sallman:

Hi, my name is David Sallman from Moffitt Cancer Center in Tampa, Florida. We just ended a really nice session on maybe the last frontier to truly derive and get novel therapy, immune therapy for patients that have myeloid malignancies. So I got to co-chair with Marion Subklewe from Germany, Dr Jae Park from Sloan Kettering, and then my colleague at Moffitt Cancer Center, Dr Andrew Kuykendall. So again, we’ve had a lot of negative efforts, but a lot of trying at the same time. I think maybe start with you, Marion. You really gave a beautiful talk on just the astronomical number of variables. I think when you don’t have therapies at work, there’s a lot of great science that happens. So maybe start with, what is your approach? What do you think will be the breakthrough? And then maybe just kind of discuss some of the challenges that we’re going through as we speak. 

Marion Subklewe:

So I don’t think that one sort of approach will solve all the problems. So I think we have to address sort of three areas, which I think are the challenge that we need to overcome. First of all, I think mono-targeting will be challenging, and there is the danger of immune escape, so I think multiple targeting has to be considered, although there will be toxicity associated. Then I really think we have to work on T-cell fitness and also consider at what stage of disease we are actually using autologous or if allogeneic T-cells might be more suitable because patients are mostly heavily pretreated and have sort of already compromised T-cell fitness. And then I really also think we have to be aware that, involving data coming out, that there is an immunosuppressive microenvironment. Probably it depends also on the genetic subtype of the AML. And we have to go for combinatorial strategies or also think of what kind of conditioning we do prior to adoptive transfer of the CAR T-cells. 

David Sallman:

I mean, Jae, maybe I’ll turn it to you. Your thoughts on this. And maybe why do we seem to keep maybe just repeating what’s being done in the other diseases? I think we’ve been talking about this for a while, but still predominantly in the US, we’ve been at single antigen and ex-US single antigen target cells. Your center is maybe starting to push that boundary. So yeah, thoughts on this and maybe then kind of moving into sort of your multi-antigen targeted approach that you guys are thinking about. 

Jae Park:

Yeah, I think I agree. I think we learned that AML is also very different than the myeloma and then the lymphoma, even though they’re within the realm of the hematology malignancies. I don’t think with traditional second-generation CAR T-cells, we’re going to be able to get deep enough remission or long enough remission to get to these patients to either get definitive therapy or even as a bridge to transplant. 

So I do think there’s a different or combinatory approach that we do need to kind of get these patients. So whether it could be armoured CAR T-cells or addressing the issue of the tumor microenvironment, T-cell fitness kind of all together, or kind of the dual targeting approaches that we can do. Even the dual targeting, I don’t know if it’s bispecific enough that we might get there. I think there has to be kind of more of a potentiating effect of the CAR T-cells. We have to ensure these T-cells proliferate. A lot of times when they do get there, they just don’t have enough stimulation to do it. So I think some of the things we’re thinking about is, what about the signaling domain? Can we make them less redundant and then less exhausted and then more proliferative to overcome their limitation? And then the cytokines are other ways to do it. So I do think we need to, I think, Marion you mentioned, be smart with these approaches, and I think the traditional approach we have seen and realized is just not enough for AML. So I think that’s kind of one approach. 

And I do think the second is that the patient selection, I think as a field that we have to think about this therapy a little bit early, we often get these patients too late, meaning at the end of or at the last resort. And I think this type of CAR T-cell therapy, you know, despite when it works well, I think it has its own side effects too. It may not be the best setting. So I think getting these patients relatively early when we realize that they are refractory or even MRD positive as the MRD is becoming much more pronounced and then commonly obtained markers, I think that will be important to get. And the T-cells might be better for those patients rather than at the end of the fourth line of therapy. 

David Sallman:

So along that, I think actually one of the most important publications in CAR-T is your New England Journal article in ALL, where you really saw in patients with the less than 5% blasts. That’s the patients that were essentially cured. So you kind of alluded to a little bit, is that it? Do we need to really go after MRD? Is this an effect or a target issue? But yeah, kind of curious your thoughts. We’re finally starting that, to at least open cohorts once we’ve cleared, but it’s been a challenge. But thoughts on MRD targeting? 

Jae Park:

Absolutely. I think we, in this workshop alone, I think solid tumors and then all these diseases, myeloma, lymphoma and then leukemia, I think we’ve consistently heard that high tumor burden is one of the worst prognostic markers. Why that is, I think we do need to do a little bit better job of whether it’s tumor driven or T-cell driven, we don’t exactly know, but I think that’s important. I think the toxicity will be better and then the efficacy will be better for these patients too. So I do think that, you know, that first we have to start, I don’t think in AML, I don’t know that certainly we have to wait until their morphologic disease. I think we already know these patients who have gotten a second induction therapy, if they have three percent leukemic cells, like they are destined to relapse. The challenges are that should we just get this patient to transplant directly with some active disease, knowing that they have a high risk of relapse, or can we try to get them to MRD negative and then get to transplant or kind of observe those patients. Ideally, the second, I think in order to get there, we need to have a little bit of an efficacy signal or the comfort level that can get these patients. But I think in that setting, the post-transplant relapse, sometimes it’s a good setting to test the hypothesis when they relapse after transplant and they have a low-level of MRD to get these patients to CAR T-cell therapy. But I do think we will learn a lot more, the patients will do better, I think we’ll get better results there. 

David Sallman:

So, Marion, you’ve done a ton of work on T-cell fitness, and maybe you could just highlight a little bit on HMA-venetoclax. Obviously, this is in the water now. Maybe it’s going to be our frontline therapy for all patients over the age of 60 independent of fitness. So, thinking about it, how do you think about utilizing HMA-VEN, the impact on T-cells, and could we think about HMA-VEN with consolidation CAR-T in frontline? 

Marion Subklewe:

Right, so we’ve started preclinically, VEN-AZA and the impact on sort of PBMCs and particularly on T-cells. And at least in preclinical setting, we saw no negative impact except B-cell depletion, which might be beneficial. And we also studied immune monitoring from patients where are actually receiving therapy compared to healthy donor controlled T-cells had no impact on, you know, proliferation, cytotoxicity. And it seems to be fair to combine or sequentially to do it in context of adaptive T-cell transfer. And also when we did it in conjunction in vitro and also in the mouse model, it worked really well and had an additive impact. And I also want to highlight there was work by Saar Gill published in Nature Medicine where they showed that cytokines of the T-cells had a negative impact on CAR T-cell mediated cytotoxicity, mainly GM-CSF, sort of conveyed resistance. And it was also shown that it leads to upregulation of BCL2 and the venetoclax can sort of overcome this. So there’s even a rationale in that context. So I would really like to see clinical trials where we combine, you know, bispecifics and CAR T-cells in conjunction with VEN-AZA. 

David Sallman:

Yeah, and maybe especially when patients can still be sensitive. I think the challenge when they’re already refractory and then we’re using it, you know, optimizing bridging therapy is an important concept. 

Marion Subklewe:

Right, and I think really, and you know, picking up what Jae already said, we need to move into earlier treatment lines. So I think with genetics and also with MRD markers, we really can identify high-risk patients. And I think it’s, you know, justified to, you know, move those at least after, you know, those finding or something to integrate these in clinical trends. 

David Sallman:

Now shifting gears a little bit, I think we have our very first MPN colleague at the iwCAR-T. This is an exciting, you know, forefront. So I think, yeah, Andrew, maybe just give a little bit of a background. How are we going to have novel therapy? Maybe talk about CALR and we could go from there. 

Andrew Kuykendall:

Yeah, it’s like a kind of more of like a field of dreams situation. If you build it, they will come, I think. I mean, so I think it’s interesting to come and we’ve kind of, obviously, learned a lot from the CAR-T development in the lymphoid space and certainly in the myeloid space it has been quite challenging. And I think we’ve wanted to kind of get involved there, but I think the diseases are very different, right? You guys are dealing with very acute diseases and high-risk diseases. And I think in MPNs, we have more indolent disease, but we have a good target, right? And so I think that’s been what’s kind of motivated us to move forward with more immune-based therapies is that calreticulin and CALR is, you know, sits on the… it’s a mutated protein, it sits on the outside of the cell. It’s only in the malignant cells. And so represents something that’s a rational target. And slowly we’ve moved in that direction, whether it’s monoclonal antibodies, T-cell redirecting antibodies, and now we’re talking a little bit about CAR-T. And maybe, I mean, especially when Jae’s talking about tumor burden and that being, you know, maybe this is more of an opportunity, right? This is a disease state that, you know, we can catch earlier forms of the disease, but then we need to match up the toxicity profile with the risk of the disease as well. And so I think it’s certainly we have a lot of excitement coming down the road with CALR. I think we have monoclonal antibodies in trials, no data yet, right, that’s publicly available. T-cell redirecting antibodies that may be a step beyond that that might be able to tackle more high-risk disease. But we also have like a more dysfunctional microenvironment also. So I think, you know, I think that we’ll definitely run into some challenges down the road. But, you know, I think that as we kind of emerge into this field, it’s important for us to start engaging and learning from kind of what’s already been learned in other disease states. 

David Sallman:

So curious, I didn’t have enough time to ask in the session. So maybe one concern, there’s a lot of bulk of disease in patients, especially when you’re having to treat them, speaking to, you know, concerns in our space. So how about after transplant? What is there? Any like developments as far as like CALR MRD? Actually, one concern I have in MRD, it’s like that’s one thing, you know? What are the targets on the MRDs left behind on an individual patient? Like completely unknown. Are there molecular subsets that have differential expression? Pretty much completely unknown in that setting. So, curious, CALR MRD – is that a thing or could it be a thing? And would it be maybe… you know relapse is still unfortunately quite high in some of these subsets of patients, should it be more of a post-allo type strategy? I’m just curious. 

Andrew Kuykendall:

It’s very reasonable, right? I mean, I think we’re, you know, several years behind the MRD field. I think recently we had New England Journal publication saying that like, if you’re positive for JAK2 30 days after then that’s not a good thing, right? I think that’s… 

David Sallman:

Should have been yours, yeah. [laughs]

Andrew Kuykendall:

Yeah, yeah. So obviously, I think we’re not there to MRD yet, but certainly I think that these types of approaches can be kind of combined either before or after transplant, right? Because this is a challenging group to transplant either way. And we don’t get, I mean, even with our current therapies, like we’re not going into transplant, you know, we have active disease. Like we’re, you know, in the chronic phase of the disease. And I think there’s still a debate of like, you know, how active can that disease be when you go into transplant? Some data would say that you can even go in with, you know, up to 10, 15% blast or so, you know, that patient’s not going to do… you know, those patients don’t do as well. But, yeah, I think that targeting these, especially because there’s not like a really solid, healthy stem cell reserve, like there’s not a lot of normal hematopoietic stem cells in these patients. And so, using this as a kind of an induction consolidating with a transplant may be an effective way to do it too. 

David Sallman:

Cool. So I think we had a great myeloid session today. We have ultra rare diseases that we’re going after. We have a lot of novel approaches pre, peri, post transplant. But again, hopefully, maybe by next year’s meeting, we’ll have some excitement towards some of our first breakthroughs. So thanks for listening.

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